Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH115IE)

• DOT Name: Voltage-gated potassium channel subunit beta-2 (KCNAB2)
• Synonyms: EC 1.1.1.-; K(+) channel subunit beta-2; Kv-beta-2; hKvbeta2
• Gene Name: KCNAB2
• Related Disease:
  Epilepsy
  Atrial fibrillation
  Pituitary adenoma
  West syndrome
  Brugada syndrome
• UniProt ID: KCAB2_HUMAN
• PDB ID: 1ZSX; 7EJ1; 7EJ2; 7WF3; 7WF4
• EC Number: 1.1.1.-
• Pfam ID: PF00248
• Sequence:
  MYPESTTGSPARLSLRQTGSPGMIYSTRYGSPKRQLQFYRNLGKSGLRVSCLGLGTWVTF
  GGQITDEMAEQLMTLAYDNGINLFDTAEVYAAGKAEVVLGNIIKKKGWRRSSLVITTKIF
  WGGKAETERGLSRKHIIEGLKASLERLQLEYVDVVFANRPDPNTPMEETVRAMTHVINQG
  MAMYWGTSRWSSMEIMEAYSVARQFNLTPPICEQAEYHMFQREKVEVQLPELFHKIGVGA
  MTWSPLACGIVSGKYDSGIPPYSRASLKGYQWLKDKILSEEGRRQQAKLKELQAIAERLG
  CTLPQLAIAWCLRNEGVSSVLLGASNADQLMENIGAIQVLPKLSSSIIHEIDSILGNKPY
  SKKDYRS
• Function: Cytoplasmic potassium channel subunit that modulates the characteristics of the channel-forming alpha-subunits. Contributes to the regulation of nerve signaling, and prevents neuronal hyperexcitability. Promotes expression of the pore-forming alpha subunits at the cell membrane, and thereby increases channel activity. Promotes potassium channel closure via a mechanism that does not involve physical obstruction of the channel pore. Promotes KCNA4 channel closure. Modulates the functional properties of KCNA5. Enhances KCNB2 channel activity. Binds NADPH and has NADPH-dependent aldoketoreductase activity. Has broad substrate specificity and can catalyze the reduction of methylglyoxal, 9,10-phenanthrenequinone, prostaglandin J2, 4-nitrobenzaldehyde, 4-nitroacetophenone and 4-oxo-trans-2-nonenal (in vitro).
• Tissue Specificity: Detected in myelinated nerve fibers in the spinal cord, in the juxtaparanodal region of the nodes of Ranvier, but also in the paranodal region . Detected in hippocampus (at protein level) . Detected in hippocampus .
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Voltage gated Potassium channels (R-HSA-1296072)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy	DISBB28L	Definitive	Genetic Variation	[1]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[2]
Pituitary adenoma	DISJ5R1X	Strong	Posttranslational Modification	[3]
West syndrome	DISLIAU9	Strong	Biomarker	[1]
Brugada syndrome	DISSGN0E	Limited	Genetic Variation	[4]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Voltage-gated potassium channel subunit beta-2 (KCNAB2) affects the response to substance of Temozolomide.	[17]
Etoposide	DMNH3PG	Approved	Voltage-gated potassium channel subunit beta-2 (KCNAB2) affects the response to substance of Etoposide.	[18]
DTI-015	DMXZRW0	Approved	Voltage-gated potassium channel subunit beta-2 (KCNAB2) affects the response to substance of DTI-015.	[17]
Mitoxantrone	DMM39BF	Approved	Voltage-gated potassium channel subunit beta-2 (KCNAB2) affects the response to substance of Mitoxantrone.	[18]

5 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[15]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[11]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[13]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Voltage-gated potassium channel subunit beta-2 (KCNAB2).	[16]

References

• [1] Loss of the potassium channel beta-subunit gene, KCNAB2, is associated with epilepsy in patients with 1p36 deletion syndrome.Epilepsia. 2001 Sep;42(9):1103-11. doi: 10.1046/j.1528-1157.2001.08801.x.
• [2] Genetic variation in KCNA5: impact on the atrial-specific potassium current IKur in patients with lone atrial fibrillation.Eur Heart J. 2013 May;34(20):1517-25. doi: 10.1093/eurheartj/ehs442. Epub 2012 Dec 21.
• [3] A pilot genome-scale profiling of DNA methylation in sporadic pituitary macroadenomas: association with tumor invasion and histopathological subtype.PLoS One. 2014 Apr 29;9(4):e96178. doi: 10.1371/journal.pone.0096178. eCollection 2014.
• [4] Dysfunction of the Voltage-Gated K+ Channel 2 Subunit in a Familial Case of Brugada Syndrome.J Am Heart Assoc. 2016 Jun 10;5(6):e003122. doi: 10.1161/JAHA.115.003122.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [17] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [18] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.